Those with HER2-positive breast cancer, regardless of hormone receptor status, who receive neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy, and fail to achieve a pCR.

Those with HER2-positive breast cancer, regardless of hormone receptor status, who undergo surgery as a first intervention and are found to have ≥ 4 positive lymph nodes.

Those with HER2-positive, hormone receptor negative breast cancer who undergo surgery as a first intervention and are found to have 1-3 positive lymph nodes.

Disease-free subjects after standard of care multi-modality therapy will be screened and HLA-typed.

Primary Outcome Measures:
Invasive Disease-free survival (DFS) [ Time Frame: Initiation of trastuzumab monotherapy through the end of the patient's fifth year of participation in the study. ] [ Designated as safety issue: No ]
Compare invasive DFS between the two treatment groups from time of initiation of trastuzumab maintenance therapy (trasuzumab monotherapy) to time of invasive local, regional or distant recurrence, new primary, or death due to any cause. Disease state will be determined by the patients' own physicians at the individual study sites during their routine follow-up screening. This will occur for all enrolled patients, regardless of randomization, approximately every three months for the first 24 months after completion of primary therapies and every six months thereafter with clinical exam, and laboratory and radiographic surveillance. The primary outcome measure of the trial is invasive DFS.

Secondary Outcome Measures:
Distant recurrence-free survival (DRFS) [ Time Frame: Initiation of trastuzumab monotherapy through the end of the patient's fifth year of participation in the study. ] [ Designated as safety issue: No ]
DRFS will be assessed as part of the patient's disease state as determined by their physician at the individual study sites during routine follow-up screening. Determination of DRFS will allow for continued follow-up on patients with local or regional recurrence.

Local and systemic toxicities [ Time Frame: From the date of initiation of the vaccine or inoculation series and booster series up to 36 months. ] [ Designated as safety issue: Yes ]
Standard local and systemic toxicities will be collected and graded per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 graded toxicity scale. For both the inoculations during the primary vaccine/inoculation series and the booster inoculations, patients will be monitored closely for one hour after inoculation with questioning, serial exams and vital signs every 15 minutes to observe for a hypersensitivity reaction. Additionally, patients will return to their study site 48-72 hours after inoculation for questioning regarding any systemic toxicity and local injection site reactions. When they return to their study site, the local reaction at the inoculation sites will be examined and measured.

Evaluate in vivo and in vitro immune responses [ Time Frame: From the date of the first inoculation of Trastuzumab monotherapy to the end of the patient's fifth year of participation in the study. ] [ Designated as safety issue: Yes ]
Immune responses will be primarily documented using the delayed type hypersensitivity (DTH) reaction and using the dextramer assay to enumerate peptide-specific CTL. Each of these measurements will be performed regardless of randomization. DTH reactions will be measured prior to initiation of the primary vaccine/inoculation series, one month ± 1 week after completion of the primary vaccine/inoculation series, and one month ± 1 week after the final booster inoculation. Dextramer measurements will be performed prior to initiating the primary vaccine/inoculation series as well as one month ± 1 week after completion of the vaccine/inoculation series. Additionally, these assays may be performed pre- and post-each booster. Alternatively, these assayed time points may also be performed all at once on frozen and banked cells.

Estimated Enrollment: 100
Study Start Date: October 2014
Estimated Study Completion Date: October 2019
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Trastuzumab + NeuVax
Patients randomized to this arm will receive vaccinations of nelipepimut-S (1000 μg) and GM-CSF (250 μg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy. Upon completion of the primary vaccination series (PVS), booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 12 months ± 2 weeks after the initiation of trastuzumab maintenance therapy, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following timepoints after initiation of trastuzumab maintenance therapy: 12 months ± 2 weeks, 18 months ± 2 weeks, 24 months ± 2 weeks and 30 months ± 2 weeks.
Biological: NeuVax vaccine
1000mcg of lyophilized E75 peptide is suspended in bacteriostatic water for injection and then frozen. At the time of vaccine administration, this frozen vial of suspended peptide is thawed and mixed thoroughly with 250mcg GM-CSF in the syringe. This constitutes the NeuVax vaccine. Patients randomized to this arm will receive vaccinations of nelipepimut-S/GM-CSF administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy.
Other Name: nelipepimut-S
Drug: Trastuzumab
Herceptin will be administered to patients every three weeks as monotherapy for one year, to be given upon completion of standard of care chemotherapy/radiotherapy. The first trastuzumab infusion will be given no sooner than three weeks and no later than 12 weeks after completion of chemotherapy/radiotherapy. Trastuzumab will be dosed at the recommended initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk.
Other Name: Herceptin
Active Comparator: Trastuzumab + GM-CSF
Patients randomized to this arm will receive inoculations of GM-CSF (250 μg) administered in an identical manner to those receiving nelipepimut-S/GM-CSF (NeuVax). Patients will be blinded as to whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone. Upon completion of the primary vaccination series (PVS), booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 12 months ± 2 weeks after the initiation of trastuzumab maintenance therapy, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following timepoints after initiation of trastuzumab maintenance therapy: 12 months ± 2 weeks, 18 months ± 2 weeks, 24 months ± 2 weeks and 30 months ± 2 weeks.
Drug: Trastuzumab
Herceptin will be administered to patients every three weeks as monotherapy for one year, to be given upon completion of standard of care chemotherapy/radiotherapy. The first trastuzumab infusion will be given no sooner than three weeks and no later than 12 weeks after completion of chemotherapy/radiotherapy. Trastuzumab will be dosed at the recommended initial loading dose of 8 mg/kg and at recommended maintenance doses of 6 mg/kg q3wk.
Other Name: Herceptin
Drug: GM-CSF
For patients randomized to the GM-CSF alone arm, they will receive inoculations of GM-CSF (250mcg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first injection will be given with the third dose of maintenance trastuzumab administered as monotherapy.
Other Names:
Leukine
Sargramostim

Detailed Description:
In this study, the investigators intend to assess the ability of the combination of trastuzumab and the HER2 vaccine nelipepimut-S (administered with the immunoadjuvant GM-CSF) given in the adjuvant setting to prevent recurrences in patients with high-risk HER2-positive breast cancer. High-risk is defined as those patients that do not achieve a pCR after neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy or those who undergo upfront surgery and are found to have greater than or equal to four positive lymph nodes regardless of hormone receptor status or 1-3 positive lymph nodes and are hormone receptor negative.

Following surgery, patients will be screened and HLA-typed (consent #1). Nelipepimut-S is a CD8-eliciting peptide vaccine that is restricted to HLA-2+ or HLA-A3+ patients (approximately two-thirds of the US population). HLA-A2+ and/or A3+ patients who meet all other eligibility criteria will be randomized to receive trastuzumab + nelipepimut-S/GM-CSF or trastuzumab + GM-CSF alone (consent #2). The trastuzumab will be administered to all patients consistent with current standard of care. Patients randomized to the nelipepimut-S/GM-CSF arm will receive vaccinations of nelipepimut-S (1000 mcg) and GM-CSF (250 mcg) administered intradermally every three weeks for six total vaccinations, 30-120 minutes after completion of trastuzumab infusion. The first vaccination will be given with the third dose of maintenance trastuzumab administered as monotherapy. Patients randomized to the GM-CSF alone arm will receive inoculations of GM-CSF (250 mcg) administered in an identical manner to those receiving nelipepimut-S/GM-CSF. Patients will be blinded as to whether they are receiving nelipepimut-S/GM-CSF or GM-CSF alone.

Upon completion of the primary vaccination/inoculation series, booster inoculations (same dose and route) will be administered every six months x 4. The first booster inoculation will occur 12 months ± 2 weeks after the initiation of trastuzumab maintenance therapy, with subsequent boosters timed every six months + 2 weeks. Boosters will therefore occur at the following timepoints after initiation of trastuzumab maintenance therapy: 12 months ± 2 weeks, 18 months ± 2 weeks, 24 months ± 2 weeks and 30 months ± 2 weeks. Booster inoculations will occur for patients randomized to receive nelipepimut-S/GM-CSF as well as patients randomized to receive GM-CSF alone, and will consist of the same treatment drugs and dosing (i.e. nelipepimut-S/GM-CSF patients will be boosted with nelipepimut-S/GM-CSF while GM-CSF alone patients will be boosted with GM-CSF alone). Patient blinding will be maintained throughout the study.

Subjects will be followed for safety issues, immunologic response and clinical recurrence. Patients will be monitored 48-72 hours after each inoculation for reaction to the inoculation as well as documentation of any adverse effects experienced. Immunologic response will be monitored primarily by in vivo delayed type hypersensitivity (DTH) reactions but also may be documented by other immunologic assays. All patients will be followed for a total of 36 months from the time of initiation of trastuzumab maintenance therapy to document disease-free status.

Eligibility

Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion criteria:

18 years or older
Eastern Cooperative Oncology Group (ECOG) performance status 0,1
AJCC stage I - III non-inflammatory, HER2-positive (according to ASCO-CAP guidelines 5) breast cancer
Completed neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy and underwent surgery with final pathology showing evidence of residual disease in the breast or axilla (residual ductal carcinoma in situ or microinvasive disease not eligible) or underwent surgery as a first intervention and was found to be pathologically node-positive: ≥ 4 positive lymph nodes (pN2 or pN3) regardless of hormone receptor status or 1-3 positive lymph nodes (pN1) if hormone receptor negative. Patients with micrometastases (pN1mi) are not eligible.
Completed an approved regimen of neoadjuvant or adjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy with plan for completion of one year of trastuzumab therapy.
Completed appropriate surgical therapy to include:
Total mastectomy and axillary staging with sentinel lymph node dissection or axillary lymph node dissection (level I/II). Patients with a positive sentinel lymph node must have undergone a completion axillary lymph node dissection.
Breast conserving surgery (BCS) and axillary staging with sentinel lymph node dissection or axillary lymph node dissection. Patients undergoing surgery as a first intervention with a positive sentinel lymph node must have undergone a completion axillary dissection level I/II unless they had clinically node negative T1-T2 tumors and fewer than 3 involved lymph nodes. Patients receiving neoadjuvant chemotherapy that have a positive sentinel lymph node must have undergone a completion axillary lymph node dissection.
Completed or receiving appropriate radiation therapy if indicated:
For patients undergoing surgery (total mastectomy) as a first intervention, post-mastectomy radiation to the chest wall, infraclavicular and supraclavicular areas is required for patients with ≥ 4 positive lymph nodes. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 1-3 positive lymph nodes, post-mastectomy radiation to the chest wall, infraclavicular, supraclavicular, and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.

For patients undergoing surgery (BCS) as a first intervention, whole breast irradiation with or without a boost, and radiation to the infraclavicular and supraclavicular areas is required for patients with ≥ 4 positive lymph nodes. Radiation to the internal mammary lymph nodes is not required but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 1-3 positive lymph nodes, whole breast irradiation with or without a boost is required. Radiation to the infraclavicular, supraclavicular, and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating medical oncologist.
For patient's undergoing mastectomy after neoadjuvant chemotherapy post-mastectomy radiation to the chest wall, infraclavicular and supraclavicular areas is required for patients presenting with clinical N2 or N3 disease or with ≥ 4 positive lymph nodes identified pathologically at the time of surgery. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 0-3 positive lymph nodes identified pathologically, post-mastectomy radiation to the chest wall, infraclavicular, supraclavicular and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.
For patient's undergoing BCS after neoadjuvant chemotherapy, whole breast irradiation with or without a boost is required. For patients with clinical N2 or N3 disease or with ≥ 4 positive lymph nodes identified pathologically at the time of surgery, radiation to the infraclavicular and supraclavicular areas is required. Radiation to the internal mammary lymph nodes is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist. For patients with 0-3 positive lymph nodes identified pathologically, radiation to the infraclavicular, supraclavicular and internal mammary areas is not required per protocol but is allowed at the discretion of the patient's treating radiation oncologist.
HLA-A2 and/or HLA-A3 positive
LVEF >50%, or an LVEF within the normal limits of the institution's specific testing (MUGA or ECHO)
Adequate organ function as determined by the following laboratory values:
ANC ≥ 1,000/μL
Platelets ≥ 75,000/μL
Hgb ≥ 9 g/dL
Creatinine ≤ 1.5 x upper limit of normal (ULN) of institution's range or Creatinine clearance ≥ 50%
Total bilirubin ≤ 1.5 ULN of institution's range
ALT and AST ≤ 1.5 ULN of institution's range
For women of child-bearing potential, agreement to use adequate birth control (abstinence, hysterectomy, bilateral oophorectomy, bilateral tubal ligation, oral contraception, IUD, or use of condoms or diaphragms)
Signed informed consent
Exclusion criteria:

AJCC Stage IV breast cancer
NYHA stage 3 or 4 congestive heart failure
Immune deficiency disease or known history of HIV, HBV, HCV
Receiving immunosuppressive therapy including chronic steroids, methotrexate, or other known immunosuppressive agents
Pregnancy (assessed by urine HCG)
Breast feeding
History of autoimmune disease
Active pulmonary disease requiring medication to include multiple inhalers (>3 inhalers including one containing steroids)
Involved in other experimental protocols except with permission of other PI
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02297698

Re: Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-r

Spent part of last week at MD Anderson, eval by MO. Recommendation was the ATEMPT clinical trial.

I am very interested in immunotherapy. If I had qualified, I was there at the right time to put my name in the hat. The clinical nurse supporting the MO was also closely following the upcoming NeuVax trial. I think we chimed in together on the 4 positive node requirement, eliminated another patient from consideration. Mittendorf's research nurse suggested I watch for any info published about a different vaccine, "AE37".

2011-0595(clinicaltrials.gov NCT No: NCT01479244)Title:PRESENT: Prevention of Recurrence in Early-Stage, Node-Positive
Breast Cancer with Low to Intermediate HER2 Expression with
NeuVax TreatmentPrincipal Investigator:Elizabeth A. MittendorfTreatment Agent:GM-CSF; NeuVaxStudy Status:OpenStudy Description:The goal of this part of the clinical research study is to learn more about the
amounts of the HER2 protein in patients who had breast cancer using the Bond
Oracle HER2 IHC System.

Re: Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-r

Remy just emailed that the information is indeed on Clinicaltrials.gov

Below is the new trial for us higher expressors who are at high risk of recurrence.
There are currently 3 sites: Houston TX, Everett WA, and Southbend IN
Please note that additional sites are planned for the future.

Quote:

Thank you again for your interest and patience in this trial. The trial is now listed on Clinical Trials under NCT02297698 and here is the link: http://clinicaltrials.gov/ct2/show/N...=neuvax&rank=1. The trial has just begun and will have additional sites over time.

Re: Phase II Trial of Combination Immunotherapy With NeuVax and Trastuzumab in High-r

To clarify who is consider High Risk

1) Neoadjuvant treatment with residual disease found at surgery

Completed neoadjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy and underwent surgery with final pathology showing evidence of residual disease in the breast or axilla (residual ductal carcinoma in situ or microinvasive disease not eligible)

2) Surgery as a first intervention and was found to be pathologically node-positive: ≥ 4 positive lymph nodes (pN2 or pN3) regardless of hormone receptor status

3) 1-3 positive lymph nodes (pN1) if hormone receptor negative.

So if you are agonizing because you did not get a complete response to chemo before surgery, if you had 4 or more positive nodes, OR if you are ER-/PR-/HER2+ and had 1-3 positive nodes - this is a great option for you.